Ataractic composition comprising 10-(1-methyl-3-piperidylmethyl)-phenothia-zine and 10-(3-dimethyl-amino-propyl)-2-chlorophenothiazine



piperidylmethyD-phenothiazlne United States Patent ATARACTIC COMPOSITION COMPRISING -(l- METHYL-3-PIPERIDYLMETHYL) PHENOTHIA- ZINE AND 10-(3-DIMETHYL-AMINO-PROPYL)-2- CHLOROPHENOTHIAZINE Henry Angus Bowes, Baie dUrfe, Quebec, Canada, as-

signor to Warner-Lambert Pharmaceutical Company, Morris Plains, N. J., a corporation of Delaware No Drawing. Application September 21, 1956 Serial No. 611,350

6 Claims. (Cl. 167-65) as well as to the desirable ettects that such drugs have produced in patients receiving them. Only too frequently does optimism of early trials give way to cautious restraint in later trials by reason of undesirable side reactions produced by such drugs. Among the drugs which have been found eltective in the management of many types of mental illness are the following two drugs identified by name and structural formula:

Mepazine or 10- (1-methyl-3- nized that some of these complications are due to the sympatholytic character of the drug.

It is an object of this invention to provide an ataractic composition which affords the beneficial efiects of Mepazine and Chlorpromazine, inmentally disturbed patients, but which does not produce the undesirable side reactions characteristic of Mepazine and Chlorpromazine. Further objects of this invention will be apparent from other disclosures set forth hereinbelow.

2,872,376 Patented Feb. 3, 1959 lCQ whereof are described hereinbelow. The said twodrugs may be used either in the form of the free base or as nontoxic acid-addition salts thereof such as the hydrochlorides, sulfates, acetates, lactates, succinates, malates and the like.

In accordance with this invention there has been found, surprisingly, that Mepazine and Chlorpromazine act synergistically in the composition of this invention. Thus the tranquillizing effect of the said composition was found to be consistently greater than might be expected from a mere summation of the tranquillizing etfects due to the two component drugs individually in the same dosage for eachas was used in the said composition, and also consistently greater than the tranquillizing efiect obtained when either of the two drugs was used alone in a dosage equal to the sum of the dosages of the said two drugs in the said composition. 'A further advantage of the composition of the invention is that the two drugs thereof are mutually antagonistic to each others complications. Further, the coadministration of the two drugs obviated the instances of the separate use of Mepazine in those patients, usually those of asthenic build, who are helped more by Chlorpromazine than by Mepazine, and conversely of the separate use of Chlorpromazine in those patients, usually of pyknic build, who are helped more by Mepazine than by Chlorpromazine. The composition of this invention may contain Mepazine and Chlorpromazine in various ratios. A predominant proportion of Chlorpromazine is indicated for use in the asthenic who is prone to feel anxiety at an adrenergic level. Mepazine would be used-in a much higher proportion than Chlorpromazine in the pyknic whose anxiety is frequently manifested at a cholinergic level. The proportion of the two drugs, in the composition of this. invention, may be adjusted to suit the individual patient after an appraisal of where this patient lies between these extremes. In most cases compositions containing equal parts of Mepazine and Chlorpromazine have been found to be broadly effective.

The administered dosage of the composition of the invention in the form of tablets, capsules, elixir and suppositories, varies broadly and may be adjusted to the requirements of the individual patients. In general, patients are started *on a total dosage of 100 to 300 mg. of the active ingredients administered three times daily whereafter the dosage is adjusted up or down until the desired degree of tranquillization is obtained. Usually the adjusted dosages for various patients fall within the range to 900 mg. daily. By the parenteral route the dosage range is usually 50 to 200 mg. daily.

Although the exact mechanism of action of the ataractic composition of this invention is not known, it is believed that the said composition works centrally by depressing the outflow of both the sympathetic and parasympathetic nervous systems, thus reducing the physical concomitan-ce of anxiety. The patient is freed from his sweating, tremor palpitations and gastrointestinal upset and thus is able to take a more objective view of his emotional problems with which he may now cope with the aid 'of psychotherapy. In addition his drive is sufiiciently reduced so that the fear of losing self-control is markedly diminished. Y

Pass the powders separately through a No. 40 screen. Mix 3 and 4, then add 1, 2 and mix. Then add serially, mixing after each addition. Granulate with 6 and pass the moist mass through a No. 16 screen. Dry at room temperature (or at 30 C.) overnight and pass the dried granules through a No. screen. Add 7 and 8 through a No. 60 screen and blend Well. Compress 105.0 mg. per tablet on fit-inch, standard concave, scored punches at 2-3 kg. hardness and 0135-0145 inch thickness.

EXAMPLE II Tablet composition Ingredients: Quantity for 1000 tablets, grams (1) Chlorpromazine hydrochloride 20.00

(2) Mepazine hydrochloride 80.00

(3) Starch, U. S. P. 32.50

(4) Methylcellulose, U. S. P., 400 cps--- 32.50

(5) Lactose, U. S. P., free-flowing 141.75 (6) Magnesium stearate, U. S. P. 3.25

To make 310.00

Pass the powders through a N0. 30 screen and blend thoroughly in the twin-cone blender. Granulate by dry compression and break up slugs through a No. 16 screen. Mix to insure even granule distribution. Compress 310 mg. per tablet on a %-inch, standard concave, scored punches at 3-5 kg. hardness and 0175-0185 inch thickness.

EXAMPLE III Tablet composition Ingredients: Quantity for 1000 tablets, grams (1) Mepazine hydrochloride 25.00

(2) Chlorpromazine hydrochloride 75.00

(3) Starch, U. S. P. 32.50

(4) Methylcellulose, U. S. P., 400 cps 32.50

(5) Lactose, U. S. P., free-flowing 141.75 (6) Magnesium stearate, U. S. P 3.25

To make 310.00

Pass the powders through a No. 30 screen and blend thoroughly in the twin-cone blender. Granulate by dry compression and break up slugs through a No. 16 screen. Mix to insure even granule distribution. Compress 310 mg. per tablet on a %-inch, standard concave, scored punches at 35 kg. hardness and 01750185 inch thick- 4 EXAMPLE 1v Tablet composition Ingredients: Quantity for 1000 tablets (1) Mepazine hydrochloride g 100.0 (2) Chlorpromazine hydrochloride g 100.0 (3) Starch, U. S. P. g 44.0 (4) Methylcellulose, U. S. P., 400 cps g 44.0 (5) Lactose, U. S. P., free-flowing g (6) Water, potable, q. s. or about m (7) Magnesium stearate, U. S. P g (8) Starch, U. S. P., dried, q. s. or about g To make g 365.0

Mix 1, 2, 3, 4 and add 5 by geometric dilution and pass the powders through a No. 30 screen. Granulate with 6 mixing until proper granule size is obtained. Dry overnight at room temperature (or at 30 C.) and pass the dried granules through a No. 14 screen on the Stokes oscillating granulator. Add 7 and 8 through a No. 40 screen and blend thoroughly. Compress 365 mg. on ym-inch, standard concave punches at 4-6 kg. hardness and 0.20-0.21 inch thickness.

EXAMPLE V Capsule composition Ingredients: Quantity for 1000 capsules, grams (1) Mepazine hydrochloride 12.5 (2) Chlorpromazine hydrochloride 12.5 (3) Lactose, U. S. P., free-flowing 415.8

(4) Magnesium stearate 9.2

To make 450.0

Pass the powders separately through a No. 40 screen. Then mix 1, 2 with 3 in divided portions, mixing after each addition. Then add 4 and blend thoroughly. Fill 450 mg. into No. 1, two-piece, hard gelatin capsules.

EXAMPLE VI Parenteral composition Ingredients: Quantity for 1000 ml. (1) Mepazine lactate g 162.0 (2) Chlorpromazine lactate g 162.0 (3) Water for injection, U. S. R, q. s ml 1000.0

Boil 800 ml. of 3 for 30 minutes, cool at room temperature in a stream of nitrogen. Add 1, 2 and enough boiled 3 to a total volume of 1000 ml. Shake well to dissolve, filter through medium porosity sintered glass filter with 3 Whatman filter paper on top into an amber bottle filled with nitrogen. Fill 2.2 ml. into amber 2 ml. constructed neck ampuls previously filled with nitrogen, and seal.

EXAMPLE VII Parenteral composition Ingredients: Quantity for 10 liters (1) Mepazine acetate g 164.0 (2) Chlorpromazine acetate g 164.0 (3) Sodium acetate, U. S. P., reagent g 100.0

(4) Acetic acid, U. S. R, q. s., pH 5.5-5.9,

about ml 75.0 (5) Water for injection, U. S. R, q. s liters 10.0

Boil 8 liters of 5 for 30 minutes, cool to room temperature in a stream of nitrogen. Add 1, 2 and 3 dis solved in about 200 ml. of boiled 5. Adjust pH to 5.5- 5.9 by addition of 4 and add enough boiled 5 to a total of liters. Shake well to dissolve, filter through a sterile Seitz filter previously rinsed with sterile water. Subsequently filter through a sterile sintered glass funnel of fine porosity, into a sterile amber bottle filled with nitrogen. Aseptically fill 2.2 ml. into sterile amber 2 ml. ampuls previously filled with nitrogen, and seal.

EXAMPLE VIII Elixir composition (9) Water, potable, q. s., about ml 1000.00

Add 1, 2 to 3 with stirring followed by 5, 7, 6 and 80 ml. of 9. When solution is complete add 8, 4 and q. s. with 9. Mix well, and filter through a coarse sintered glass funnel.

EXAMPLE IX Suppositories composition- Quantity for 1000 g., g. 1) Mepazine hydrochloride 50.0 (2) Chlorpromazine hydrochloride 50.0 (3) Cocoa butter substitute, q. s 1000.0

Melt 3 on a steam bath. Add 1, 2 and stir until uni- Ingredients:

1 form. At about 40 pour into chilled suppository molds.

Allow to solidify at room temperature for about minutes then keep at 5 C. for about 30 minutes.

EXAMPLE X Suppositories composition Ingredients: Quantity for 1000 g., g. (1) Mepazine hydrochloride 30.0 (2) Chlorpromazine hydrochloride 70.0

(3) Cocoa butter substitute, q. s 1000.0

The suppositories are prepared in the manner described .in Example IX.

6 EXAMPLE XI Suppositories composition Quantity for 1000 g., g. (l) Mepazinc hydrochloride 80.0 (2) Chlorpromazine hydrochloride 20.0 (3) Cocoa butter substitute, q. s 1000.0

Suppositories are prepared in the manner described in Example IX.

Since certain changes may be made in the compositions above described without departing from the scope of this invention, it is intended that all matter contained in the above description shall be interpreted as illustrative, and not in a limiting sense.

What is claimed is:

1. An ataractic composition having as an active ingredient a mixture of substance A and substance B, said substance A being a member selected from the group consisting of 10-(1-methy1-3-piperidylmethyl)phenothiazine and the nontoxic salts thereof, and said substance B being a member selected from the group consisting of 10-(3dimethylaminopropyl)-2-chlorophenothiazine and the nontoxic salts thereof, said composition also comprising a pharmaceutical carrier.

2. The composition of claim 1 where said composition is in the form of tablets.

3. The composition of claim 1 wherein said composition is in the form of capsules.

4. The composition of claim 1 wherein said composition is in the form of an elixir.

5. The composition of claim 1 wherein said composition is in the form of a parenteral preparation.

6. The composition of claim 1 wherein said composition is in the form of suppositories.

Ingredients:

References Cited in the file of this patent Eiber: I. A. M. A., vol. 158, No. 9, July 2, 1955, pp. 730-731.

Eiber: Arch. Neurol. Psychiat., vol. 74, July 1955, pp. 36 39.

Barsa et al.: Am. J. Psychiat., vol. 111, April 1955, p. 780.

Wright: Ann. N. Y. Acad. Sci., vol. 61, April 15, 1955, p. 178 pert.

I. A. M. A.: vol. 161, No. 3, May 19, 1956, p. 265. 

1. AN ATARATIC COMPSOITION HAVING AS AN ACTIVE INGRESIENT A MIXTURE OF SUBSTANCE A AND SUBSTANCE B, SAID SUB STANCE A BEING A MEMBER SELECTED FROM THE GROUP CONSISTING OF 10-(1-METHYL-3-PIPERIDYMETHYL) PHENOTHIAZINE AND THE NONTOXIC SALTS THEREOF, AND SAID SUBSTANCE B BEING A MEMBER SELECTED FROM THE GROUP CONSISTING OF 10-(3-DIMETHYLAMINOPROPYL)-2-CHLOROPHENOTHIAZINE AND THE NONTOXIC SALTS THEREOF, SAID COMPOSITION ALSO COMPRISING A PHARMACEUTICAL CARRIER. 